Novel bisphenoxy carboxylic acid derivatives and their salts

ABSTRACT

Bisphenoxy carboxylic acid derivatives useful as an antiarteriosclerosis agent with good absorbability and low toxicity, which are novel compounds represented by the general formula, ##STR1## wherein R 1  and R 2  represent hydrogen atoms or lower alkyl groups and A represents ##STR2## (wherein in case R 3  is a hydrogen atom, R 4  represents an amino-lower-alkyl group, an N-lower-alkylaminoalkyl group, a heterocyclic group, or a heterocyclic group-substituted alkyl group; or R 3  and R 4  may join through an intermediary hetero atom to form a heterocyclic group and if said hetero atom is a nitrogen atom, this nitrogen atom can bear a lower alkyl group as a substituent) or ##STR3## (wherein R 5  represents a hydrogen atom, a hydroxyalkyl group or a derivative thereof, and R 6  represents a hydroxyalkyl group or a heterocyclic group; or R 5  and R 6  may join to form a cyclic group, or may join through another intermediary hetero atom to form a heterocyclic group and if said hetero atom is a nitrogen atom, this nitrogen atom can bear a lower alkyl group as a substituent), are prepared by reacting a bisphenoxy acid represented by the general formula, ##STR4## wherein R 1  and R 2  have the same meanings as defined above, or a reactive derivative thereof with a hetero atom-containing alcohol compound represented by the general formula, ##STR5## wherein R 3  and R 4  have the same meanings as defined above, an amine derivative represented by the general formula, ##STR6## wherein R 5  and R 6  have the same meanings as defined above, or a salt thereof. Alternatively, the bisphenoxy carboxylic acid derivatives represented by the said general formula (I), wherein A is ##STR7## R 5  is hydrogen and R 6  is a hydroxyalkyl group, are prepared by heating a bisphenoxy acid derivative represented by the general formula, ##STR8## wherein R 1  and R 2  have the same meanings as defined above and X represents an alkylene chain.

This is a continuation, of application Ser. No. 255,244, filed May 19,1972, now abandoned.

This invention relates to novel anti-atherosclerosis agents. Moreparticularly, the invention pertains to novel agents which are usefulfor the lowering of elevated levels of cholesterol or lipids.

Atherosclerosis is an adult disease for which there is no knownsatisfactory cure. Although the cause for atherosclerosis is not yetknown in spite of discussions in the academic circles, it has broadlybeen recognized that one of the most significant histopathologicalmanifestations of atherosclerosis is the deposition of lipids in theblood. Accordingly, research has been directed to the disturbedmetabolism of lipids, and attention has been given to theextraordinarily elevated level of cholesterol in the blood.

A number of experimental and clinical facts have been reported, whichindicate the relationship between atherosclerosis and elevated bloodcholesterol or lipid level. Hence, the development of agents to reducethe elevated blood cholesterol or lipid level is considered extremelyimportant for the prevention of atheroclerosis.

Concentrated effects have heretofore been made for the development ofsuch agents for lowering cholesterol or lipids and a number of compoundshave been tested clinically, but none of them have proved to becompletely satisfactory. Some of them are fairly effective but producesignificantly harmful side effects, and others have inadequateeffectiveness, so that they are required to be administered in largedoses.

A group of compounds practically employed presently for the abovepurpose includes ethyl α-(p-chlorophenoxy)-isobutyrate (clofibrate).

The present inventors have found a group of novel compounds which areeffective as cholesterol-lowering agents and which are substantiallynon-toxic and less hepatomegalic than clofibrate.

An object of the present invention is to provide novelbisphenoxycarboxylic acid derivatives usable as anti-atherosclerosisagents which have prominent effects and extremely high in admissibility.

Another object of the invention is to provide an economical andindustrially advantageous process for producing the above-mentionedbisphenoxycarboxylic acid derivatives.

A further object of the invention is to provide a pharmaceuticalcomposition containing such antiatherosclerosis agent.

Other objects and merits of the invention will be apparent from thefollowing description.

In order to accomplish these objects, the present invention providesnovel bisphenoxycarboxylic acid derivatives of the formula, ##STR9##wherein R₁ and R₂ represent hydrogen atoms or lower alkyl groups and Arepresents ##STR10## (wherein in case R₃ is a hydrogen atom, R₄represents an amino-lower-alkyl group, an N-lower-alkylaminoalkyl group,a heterocyclic group, or a heterocyclic group-substituted alkyl group;or R₃ and R₄ may join through an intermediary hereto atom to form aheterocyclic group and if said hetero atom is a nitrogen atom, thisnitrogen atom can bear a lower alkyl group as a substituent) or##STR11## (wherein R₅ represents a hydrogen atom, a hydroxyalkyl groupor a derivative thereof, and R₆ represents a hydroxyalkyl group or aheterocyclic group; or R₅ and R₆ may join to form a cyclic group, or mayjoin through another intermediary hetero atom to form a heterocyclicgroup and if said hetero atom is a nitrogen atom, this nitrogen atom canbear a lower alkyl group as a substituent or acid addition salts.

Phenoxy acid derivatives for use as starting materials, which arerepresented by the general formula, ##STR12## wherein R₁ and R₂represents hydrogen atoms or lower alkyl groups, were first synthesizedby the present inventors by any one of the procedures as shown by thefollowing reaction scheme; ##STR13## wherein R₁ and R₂ are as definedabove, and Y is lower alkyl.

The phenoxy carboxylic acid derivatives of this invention may beobtained by reacting a bisphenoxy acid represented by the generalformula, ##STR14## wherein R₁ and R₂ have the same meanings as definedabove, or a reactive derivative thereof with a hetero atom-containingalcohol represented by the general formula, ##STR15## wherein R₃ and R₄have the same meanings as defined above, or with an amine derivativerepresented by the general formula, ##STR16## wherein R₅ and R₆ have thesame meanings as defined above, or a salt thereof.

The reaction itself in this invention can be satisfactorily carried outby the conventional procedure.

Some of the compounds of this invention can also be synthesizedaccording to the following new reaction scheme found by the presentinventors during the course of researchers in connection with thepresent invention: An amino ester represented by the general formula,##STR17## wherein R₁ and R₂ have the same meanings as defined above andX represents an alkylene chain, is heated preferably at a moderatetemperature of 50° to 100° C. to form a hydroxyalkyl acid amiderepresented by the general formula (I), provided that A is ##STR18## R₅is a hydrogen atom and R₆ is a hydroxyalkyl group.

The term "reactive derivative of carboxylic acid" used herein meansderivatives such as a carboxylic acid halide and acid anhydride.

The term "alkylene chain" means ethylene, trimethylene ortetramethylene.

Thus, the reaction of a carboxylic acid halide of a compound representedby the general formula (II) with an alcohol represented by the generalformula (III) can be satisfactorily carried out in an inert organicsolvent such as, for example, benzene, toluene, ether, dioxane,tetrahydrofuran, acetone, methyl isobutyl ketone, chloroform, carbontetrachloride or the like, or in a mixed solvent containing said organicsolvent and water, in the presence or absence of an organic base such astrimethylamine, triethylamine, diethylaniline, pyridine or the like, oran inorganic base such as sodium hydroxide, potassium hydroxide, sodiumcarbonate, potassium carbonate, sodium hydrogen carbonate or the like.

The reaction of a carboxylic acid of the general formula (II) with ahetero atom-containing alcohol can be carried out in the above-mentionedinert solvent in the presence of a dehydration-condensation agent suchas, for example, hydrochloric acid, sulfuric acid, potassium hydrogensulfate, sodium hydrogen sulfate, toluenesulfonic acid, an ion-exchangeresin, a dialkyl carbodiimide, or the like, to synthesize advantageouslythe objective ester.

The objective ester can also be obtained by first reacting a carboxylicacid of the formula (II) with a chloroformate ester, and then furtherreacting with an alcohol represented by the general formula (III), thatis, by a so-called mixed-acid-anhydride method.

In the case where the hetero atom in the general formula (III) isnitrogen atom and is in a grouping of primary or secondary amine, it isdesirable to protect said nitrogen atom with a benzyloxycarbonyl group,trityl group, o-nitro-phenylsulfinyl group, or the like, which caneasily be split after the objective ester has been formed.

Typical examples of the hetero atom-containing alcohols for use in thisinvention include amino-alkyl alcohols such as ethanolamines andpropanol-amines, and derivatives thereof, pyridylalkyl alcohols andderivatives thereof, pyridylalkyl alcohols and derivatives thereof,piperidyl alcohols and derivatives thereof, piperazyl alcohols andderivatives thereof, pyrrolidyl alcohols and derivatives thereof,pyrrolyalkyl alcohols and derivatives thereof, morpholyl alcohols andderivatives thereof, thiophenylalkyl alcohols, thiazonylalkyl alcohols,oxazolealkyl alcohols, furanylalkyl alcohols, and pyranyl alcohols.

The reaction of an acid halide as a reactive derivative of thebisphenoxy acid of the general formula (II) with an amine represented bythe general formula (IV) can be carried out in an inert organic solventsuch as benzene, toluene, a petroleum hydrocarbon, ether, dioxane,tetrahydrofuran, acetone, methyl ethyl ketone, methyl isobutyl ketone,chloroform, or carbon tetrachloride, or water, or a mixed solventcomprising water and said organic solvent, in the presence or absence ofan organic base such as trimethylamine, triethylamine, diethylaniline,or pyridine, or an inorganic base such as sodium hydroxide, potassiumhydroxide, sodium carbonate, potassium carbonate, or sodium hydrogencarbonate, to obtain an acid amide derivative represented by the generalformula (I).

The reaction of a carboxylic acid of the general formula (II) with anamine represented by the general formula (IV) or with said amine, ifnecessary, after having other reactive groups protected by protectinggrups can be carried out by using both reactants in equimolar amounts oreither one of them in excess, in the absence or presence of a catalystsuch as sulfuric acid, potassium hydrogen sulfate, toluenesulfonic acid,toluenesulfonic acid chloride, or acidic or basic ion-exchange resins,e.g. IRA-400, IR-50 or IR-120, in a solvent, if necessary, such asbenzene, toluene or xylene, at 60° to 140° C. for several to severaltens hours, while removing or without removing the water which is formedduring the reaction. Alternatively, the objective amide compoundrepresented by the general formula (I) can be obtained by dissolvingboth reactants in an inert solvent, as mentioned above in the case ofthe reaction between an acid halide and an amine, and reacting in thepresence of a dehydrating catalyst such as a dialkyl carbodiimide atpreferably -15° to 30° C. for several tens minutes to several tenshours.

The objective amide compound can also be obtained by first reacting acarboxylic acid of the general formula (II) with a reagent such as achloroformate ester which forms a mixed-acid-anhydride at preferably-40° to 40° C., and then reacting with an amine represented by thegeneral formula (IV) at preferably -40° to 40° C.

Further, the objective amide compound represented by the general formula(I) can be obtained by reacting an ester derivative of a carboxylic acidof the general formula (II) in which hydroxyl groups have been replacedby lower alkoxy groups, nitrophenoxy groups, nitrobenzyloxy groups, orthe like, with an amine represented by the general formula (IV) in asuitable solvent such as methanol, ethanol, other alcohols, benzene,toluene, or the like, in the presence or absence of a catalyst such assodium alcoholate, trialkylamine, potassium hydroxide, sodium hydroxide,potassium carbonate, sodium carbonate, or other inorganic bases.

Typical examples of amines represented by the general formula (IV) foruse in this invention include aminoalkyl alcohols such as ethanolamine,propanolamine, diethanolamine, and derivatives thereof,heterocycloaliphatic compounds such as pyrrolidine, piperidine,piperazine, morpholine, and derivatives thereof, heterocyclic aminederivatives such as furan, thiophene, pyrrole, oxazole, thiazole,imidazole, pyrazole, pyran, pyridine, etc.

The compounds represented by the general formula (I) can be alsosynthesized using the catalysts of phosphine and mercaptoamine or thelike from carboxylic acid represented by the formula (II) and alcoholsrepresented by the formula (III) or amines represented by the formula(IV), by method of Oxidation-Reduction condensation disclosed inTetrahedron Letters 1901 - 1904 (1970) or J. Am. Chem. Soc., 90, 4490(1964).

The acid addition salts include the salt of the amine derivative (in thegeneral formula (I), A contains amine group) with inorganic or organicacid such as hydrochloric acid, sulfuric acid, nitric acid, acetic acid,oxalic acid, tartaric acid, citric acid, malic acid, succinic acid,maleic acid, fumaric acid and the like.

The acid addition salts of the compounds which were obtained by thepresent invention have also good pharmaceutical properties, forinstance, a high solubility and dispersibility or a favourable pH valuein the solution.

The present invention further provides a pharmaceutical compositioncontaining a bisphenoxy carboxylic acid derivative of the formula (I).

The cholesterol-lowering agents of this invention may be, for example,orally administered.

Usually the amount orally administered is 0.2 g - 1.5 g per day/humanadult. The cholesterol-lowering agent may be in any suitable form whichis conventional for oral administration. Thus, it may be encased in acapsule, or it may be in a liquid form, in a tablet form, or in a powderform. In preparing the agents in these various forms, the activecompound may be mixed with or impregnated in a suitable solid carrier.

The process of the present invention is illustrated in more detail bythe following examples, but it is not intended to limit the invention tothem.

EXAMPLE 1 ##STR19##

In 150 ml of anhydrous benzene, are dissolved 6 g of1,1-bis[4'-(1"-carboxy-1"-methylpropoxy)-phenyl]-cyclohexane and 30 g ofthionyl chloride, and refluxed for 2 hours with stirring. The reactionmixture is concentrated under reduced pressure to obtain a crude acidchloride. Into another solution prepared by dissolving 2.6 g of3-dimethylaminopropanol and 2.6 g of triethylamine in 150 ml ofanhydrous toluene, is added with stirring the above-obtained crude acidchloride over a period of 30 minutes at 10° C. After being stirred atthe same temperature for 2 hours, the mixture is left standingovernight. The reaction mixture is washed with cold sodium carbonate,then washed with water, and further treated with activated carbon toobtain an ester. The ester thus obtained is dissolved in ether and dryhydrogen chloride gas is introduced therein to obtain a hydrochloride.The hydrochloride is thoroughly washed with ether, dehydrochlorinatedwith an aqueous solution of sodium carbonate, washed with water, driedand concentrated to obtain 5.0 g of the objective ester, n_(D) ²⁵1.5212.

    ______________________________________                                        Elementary analysis:                                                                       Found         Theoretical                                        ______________________________________                                        C, %         72.29         72.47                                              H, %         9.09          8.82                                               N, %         3.93          4.24                                               ______________________________________                                    

EXAMPLE 2 ##STR20##

In a manner similar to that in Example 1, a crude acid chloride isobtained from 6 g of1,1-bis[4'-(1"-carboxy-1"-methylpropoxy)-phenyl]cyclohexane, 30 g ofthionyl chloride and 120 ml of anhydrous benzene. The crude acidchloride is reacted with 3 g of diethylaminoethanol and 3 g oftriethylamine and treated in a manner similar to that in Example 1, toobtain 5.9 g of the objective ester, n_(D) ²⁴ 1.5272.

    ______________________________________                                        Elementary analysis:                                                                       Found         Theoretical                                        ______________________________________                                        C, %         72.02         72.03                                              H, %         9.45          9.37                                               N, %         4.07          4.20                                               ______________________________________                                    

EXAMPLE 3 ##STR21##

7.1 Grams of 1,1-bis[4'-(1"-carboxy-1"-methylpropoxy)-phenyl]cyclohexaneand 4.9 g of 2-diisopropylaminoethanol hydrochloride are refluxed inbenzene in the presence of 0.8 g of p-toluenesulfonic acid for 6 hours.Refluxing is continued while removing the formed water azeotropicallywith benzene. The reaction mixture is treated in a manner similar tothat in Example 1 to obtain 3.1 g of the objective ester, n_(D) ²⁵1.5195.

    ______________________________________                                        Elementary analysis:                                                                       Found         Theoretical                                        ______________________________________                                        C, %         73.07         73.09                                              H, %         9.60          9.76                                               N, %         3.72          3.87                                               ______________________________________                                    

EXAMPLE 4 ##STR22##

In a manner similar to that in Example 1, a crude acid chloride isobtained from 4.7 g of1,1-bis[4'-(1"-carboxy-1"-methylpropoxy)-phenyl]cyclohexane, 30 g ofthionyl chloride and 100 ml of benzene. The crude acid chloride isreacted with 3.9 g of N-benzyloxycarbonylaminoethanol and 2.3 g oftriethylamine according to the procedure in Example 1. The reactionmixture is washed successively with dilute hydrochloric acid, water, anaqueous solution of sodium carbonate, and water. The washed reactionmixture is dried and treated with activated carbon. The resulting oilysubstance is purified by chromatography to obtain 4.0 g of the objectiveester, n_(D) ²² 1.5501.

    ______________________________________                                        Elementary analysis:                                                                       Found         Theoretical                                        ______________________________________                                        C, %         70.07         70.05                                              H, %         7.11          7.10                                               N, %         3.35          3.40                                               ______________________________________                                    

EXAMPLE 5 ##STR23##

Hydrogen is introduced, at room temperature, into 150 ml of ethanolcontaining 1.8 g of di-N-benzyloxycarbonylaminoethanol ester of1,1-[4'-(1"-carboxy-1"-methylpropoxy)-phenyl]cyclohexane and 0.1 g ofdissolved hydrogen chloride gas, in the presence of a palladium-carboncatalyst. The reaction is complete in 2 hours, the end point beingconfirmed by disappearance of the spot due to the starting material inthin layer chromatography. Then, the catalyst is filtered off and thesolvent is removed by distillation. The remaining oily substance iscrystallized from ether to obtain 1.4 g of the objective hydrochloride,melting at 114° C. (decomp).

    ______________________________________                                        Elementary analysis:                                                                       Found         Theoretical                                        ______________________________________                                        C, %         61.05         61.23                                              H, %         7.76          7.71                                               N, %         4.40          4.46                                                Cl, %       11.47         11.30                                              ______________________________________                                    

EXAMPLE 6 ##STR24##

In 80 ml of dichloromethane, are dissolved 4.3 g of1,1-bis[4'-(1"-carboxy-1"-methylethoxy)phenyl]cyclohexane and 2.2 g oftriethylamine. To the resulting solution cooled below -5° C., is addeddropwise with vigorous stirring 2.6 g of ethyl chloroformate over aperiod of 30 minutes. After being stirred at the same temperature forone hour, the mixture is admixed with a dichloromethane solutioncontaining 3 g of pyridine carbinol while maintaining the innertemperature at -5° to 10° C. After being stirred for one hour at thesame temperature and another one hour at room temperature, the reactionmixture is treated and purified as mentioned in Example 1 to obtain 3.4g of the objective ester, n_(D) ²³ 1.5669.

    ______________________________________                                        Elementary analysis:                                                                       Found         Theoretical                                        ______________________________________                                        C, %         73.49         73.29                                              H, %         6.78          6.86                                               N, %         4.38          4.50                                               ______________________________________                                    

EXAMPLE 7 ##STR25##

In a manner similar to that in Example 1, a crude acid chloride isobtained from 4.3 g of1,1-bis[4'-(1"-carboxy-1"-methylethoxy)phenyl]cyclohexane, 30 g ofthionyl chloride and 80 ml of anhydrous benzene. The acid chloride isreacted with 2.3 g of 4-hydroxy-N-methylpiperidine and 2.1 g oftriethylamine and treated as mentioned in Example 1 to obtain 2.1 g ofthe objective ester, n_(D) ²² 1.5300.

    ______________________________________                                        Elementary analysis:                                                                       Found         Theoretical                                        ______________________________________                                        C, %         71.89         71.89                                              H, %         8.55          8.57                                               N, %         4.30          4.41                                               ______________________________________                                    

EXAMPLE 8 ##STR26##

In a manner similar to that in Example 1, a crude acid chloride isobtained from 4.7 g of1,1-bis[4'-(1"-carboxy-1"-methylpropoxy)-phenyl]cyclohexane, 30 g ofthionyl chloride, and 100 ml of benzene. The acid chloride is reactedwith 3 g of 3-pyridinecarbinol dissolved in 100 ml of toluene, thentreated and purified as mentioned in Example 1 to obtain 5.1 g of theobjective ester, n_(D) ²⁶ 1.5671.

    ______________________________________                                        Elementary analysis:                                                                       Found         Theoretical                                        ______________________________________                                        C, %         73.90         73.82                                              H, %         7.20          7.12                                               N, %         4.18          4.30                                               ______________________________________                                    

EXAMPLE 9 ##STR27##

In 100 ml of dichloromethane, are dissolved 4.7 g of1,1-bis[4'-(1"-carboxy-1"-methylpropoxy)phenyl] cyclohexane and 2.2 g oftriethylamine. To the solution, is added with stirring 2.6 g of ethylchloroformate dropwise over a period of 40 minutes at -5° C. To themixture, after being stirred at the same temperature for 1.5 hours, isadded a solution of 1.3 g of ethanolamine in 20 ml of dichloromethanedropwise over a period of 30 minutes at a temperature below -5° C. Afterthe mixture is stirred at said temperature for one hour, the coolingbath is removed and the temperature of the mixture is brought to roomtemperature in 30 minutes. The mixture is stirred at room temperaturefor two hours, then concentrated and transferred with ether to aseparatory funnel, in which the mixture is washed successively with colddilute hydrochloric acid, water, an aqueous solution of sodiumcarbonate, and water. On drying and concentrating 3.4 g of the objectivecrude amide is obtained. On further purification by chromatography usingsilica gel, 2.7 g of the objective purified amide compound is obtained.

    ______________________________________                                        Elementary analysis:                                                                      C          H          N                                           ______________________________________                                        Theoretical, %                                                                            69.28      8.36       5.05                                        Found, %    69.22      8.36       4.93                                        ______________________________________                                    

Acetyl derivative:

The above-obtained amidoalcohol is acetylated with acetyl chloride in acustomary way to yield an amidoacetate compound, n_(D) ²² 1.5345.

    ______________________________________                                        Elementary analysis:                                                                      C          H          N                                           ______________________________________                                        Theoretical, %                                                                            67.69      7.89       4.39                                        Found, %    67.62      7.82       4.40                                        ______________________________________                                    

EXAMPLE 10 ##STR28##

In 100 ml of anhydrous toluene, are dissolved 4.9 g of1,1-bis[4-(1"-carboethoxy-1"-methylethoxy)-phenyl]cyclohexane and 2.0 gof ethanolamine. After being admixed with 0.1 g of sodium methylate, thesolution is refluxed with stirring for 20 hours.

After being cooled, the reaction mixture is washed successively withcold dilute hydrochloric acid, water, an aqueous sodium carbonatesolution, and water. Then, the mixture is dried over anhydrous sodiumsulfate and concentrated to yield 3.4 g of a crude amidoalcoholcompound.

In 50 ml of anhydrous toluene, are dissolved 3.3 g of the above-obtainedcrude amidoalcohol compound and 1.4 g of triethylamine. To the solution,is added 1.1 g of acetyl chloride dropwise over a period of 20 minuteswith stirring at 0° to 5° C. The mixture is stirred at said temperaturefor 30 minutes, then at room temperature for 3 hours, and left standingovernight. The reaction mixture is washed with cold dilute hydrochloricacid, and then with water. The mixture is dried over anhydrous sodiumsulfate, concentrated, and purified by chromatography using silica gel,to yield 2.5 g of the objective amidoacetate compound, n_(D) ²⁴ 1,.5341.

    ______________________________________                                        Elementary analysis:                                                                      C          H          N                                           ______________________________________                                        Theoretical, %                                                                            66.86      7.59       4.59                                        Found, %    66.90      7.61       4.54                                        ______________________________________                                    

EXAMPLE 11 ##STR29##

In 100 ml of toluene, are dissolved 6 g of1,1-bis[4'-(1"-carboxy-1"-methylpropoxy)phenyl]cyclohexane and 30 g ofthionyl chloride, and the solution is refluxed for 2 hours. The excessof thionyl chloride and toluene are removed by distillation underreduced pressure. Fifty milliliters of toluene is again added andremoved by distillation under reduced pressure. This treatment isrepeated twice more to obtain a crude acid chloride free from thionylchloride.

To a solution of 4.5 g of morpholine and 2.7 g of triethylamine in 100ml of anhydrous toluene, is added with stirring, at 0° to 5° C., asolution of the above-obtained crude acid chloride in 50 ml of anhydroustoluene dropwise over a period of one hour. Stirring is continued for 2hours at the said temperature, then for another 2 hours at roomtemperature, and for further 2 hours at 50° C. The reaction mixture iswashed successively with an aqueous dilute solution of hydrochloricacid, water, an aqueous sodium carbonate solution, and water. Afterremoval of the solvent, the reaction product is recrystallized frombenzene-petroleum ether and then from benzene-ethyl acetate to obtain5.2 g of the objective amide compound, melting at 149° - 150° C.

    ______________________________________                                        Elementary analysis:                                                                      C          H          N                                           ______________________________________                                        Theoretical, %                                                                            71.29      8.19        4.61                                       Found, %    71.25      8.31       4.62                                        ______________________________________                                    

EXAMPLE 12 ##STR30##

In 50 ml of toluene, are dissolved 5 g of1,1-bis[4'-(1"-carboxy-1"-methylpropoxy)phenyl]cyclohexane, 3 g ofN-methylpiperazine and 1 g of potassium hydrogen sulfate. The solutionis refluxed for 30 hours in an apparatus equipped with a water-separatorto effect dehydration reaction. After cooling, the reaction mixture issuccessively washed with cold aqueous sodium carbonate and water toobtain 4.0 g of the objective amide compound, melting at 65° to 67° C.

    ______________________________________                                        Elementary analysis:                                                                      C          H          N                                           ______________________________________                                        Theoretical, %                                                                            72.29      8.18       8.61                                        Found, %    72.11      8.92       8.80                                        ______________________________________                                    

Hydrochloride of the objective compound, melting at 160° - 161° C.(decomp.)

EXAMPLE 13 ##STR31##

In 150 ml of toluene, are dissolved 2.2 g of 2-aminopyridine and 4 g ofdicyclohexyl carbodiimide. To the solution cooled to -5° C., is added,with stirring, dropwise over a period of 10 minutes 4.5 g of1,1-bis[4'-(1"-carboxy-1"-methylpropoxy)phenyl]cyclohexane dissolved in100 ml of ether and cooled to -5° C. After stirring the mixture for 20minutes at said temperature, the cooling bath is removed and stirring iscontinued for further 2 hours at room temperature. After standingovernight, the reaction mixture is filtered and the filtrate is admixedwith 0.2 g of acetic acid. After stirring for 30 minutes, the reactionmixture is filtered and the filtrate is washed successively with water,an aqueous sodium carbonate solution, and water. Hydrogen chloride gasis introduced into the solution and then the solution is concentrated toobtain 4.1 g of the objective amide hydrochloride, melting at 118° -119° C.

    ______________________________________                                        Elementary analysis:                                                                       C        H        N      Cl                                      ______________________________________                                        Theoretical, %                                                                             65.79    6.68     8.08 10.22                                     Found, %     65.63    7.04     7.94 10.13                                     ______________________________________                                    

EXAMPLE 14 ##STR32##

In 50 ml of benzene, are dissolved 4.6 g of1,1-bis[4'-(1"-carboxy-1"-methylethoxy)phenyl]cyclohexane and 30 g ofthionyl chloride, and the solution is refluxed for 2 hours. A crude acidchloride is obtained in a manner similar to that in Example 11. To asolution of 3.9 g of N-benzyloxycarbonylaminoethanol and 2.3 g oftriethylamine in 50 ml of benzene, is added the above-obtained crudeacid chloride dissolved in 50 ml of benzene dropwise over a period ofone hour at 0° to 5° C. The mixture is treated in a manner similar tothat in Example 11 and purified by chromatography using silica gel toobtain 4.7 g of N-benzyloxycarbonylamino ester compound, n_(D) ²⁴1.5500.

    ______________________________________                                        Elementary analysis:                                                                      C          H          N                                           ______________________________________                                        Theoretical, %                                                                            69.50      6.85       3.52                                        Found, %    69.39      6.90       3.41                                        ______________________________________                                         ##STR33##

4 Grams of N-benzyloxycarbonylamino ester compound obtained in 1) isdissolved in 20 g of ethanol and admixed with 1 g of palladium-carbon.Theoretical amount of hydrogen is added to the solution at ordinarypressure in two hours. After removal of palladium-carbon by filtration,the solution is concentrated at 60° to 70° C. The concentrate isdissolved in ether and washed successively with a cold aqueous solutionof hydrochloric acid, water, an aqueous sodium carbonate solution, andwater. The washed solution is dried over anhydrous sodium sulfate andconcentrated by heating at 60° to 70° C. to obtain 3.0 g of anamidoalcohol compound.

3. 2.0 Grams of the amidoalcohol compound and 1.0 g of dimethylanilineare dissolved in 50 ml of benzene and treated in a manner similar tothat in Example 10 to obtain 1.8 g of the objective acetylamidecompound, n_(D) ²³ 1.5340. PG,27

    ______________________________________                                        Elementary analysis:                                                                      C          H          N                                           ______________________________________                                        Theoretical, %                                                                            66.86      7.59       4.59                                        Found, %    66.70      7.62       4.51                                        ______________________________________                                    

The cholesterol lowering activity of the above-prepared compounds wastested by the following method.

Male Wistar rats weighing 130 g to 160 g were divided into severalexperimental groups, 5 to ten animals in each group.

Test compounds were administered orally by a stomach tube. The period oftreatment was 7 days.

At the end of the test period, blood samples were collected from theinferior vena cava under light ether anesthesia and the weight of liverwas recorded.

Serum cholesterol and serum triglycerides were determined.

Cholesterol lowering effect was expressed as percentage of serumcholesterol levels of control group as shown in the following Table 1.In the Table 1, compounds are referred to by number of theabove-mentioned examples.

                  Table I                                                         ______________________________________                                                                              Relative                                Com-  Dura-    Serum   liver                                                  pound Dose     tion    Cholesterol                                                                           Triglycerides                                                                          weight.sup.(2)                        No.   (mg/kg)  (days)  index.sup.(1)                                                                         index.sup.(1)                                                                          index.sup.(1)                         ______________________________________                                        1     30       7       81      57       105                                   2     30       7       83      57       109                                   3     30       7       73      45       102                                   4     30       7       79      53       111                                   5     30       7       80      56       108                                   6     30       7       81      50       100                                   7     30       7       80      58       106                                   8     30       7       75      60       111                                   9     100      7       84      74       104                                   10    100      7       87      80       103                                   11 100                                                                              7        80      86      103                                            12    100      7       78      73       108                                   13    100      7       81      77        94                                   Clofi-                                                                        brate 300      7       90      76       144                                   ______________________________________                                         ##STR34##                                                                    .sup.(2) Relative liver weight =                                               Liver weight (g)/100 g of body weight                                    

What is claimed is:
 1. A bisphenoxy carboxylic acid derivativerepresented by the general formula, ##STR35## wherein R₁ and R₂represent lower alkyl groups, R₃ is hydrogen and R₄ represents anamino-lower-alkyl group or an N-lower-alkylaminoalkyl group, and itsacid addition salt.
 2. The compound according to claim 1 of the formula,##STR36## and its acid addition salt.
 3. The compound according to claim1 of the formula, ##STR37## and its acid addition salt.
 4. The compoundaccording to claim 1 of the formula, ##STR38## and its acid additionsalt.
 5. The compound according to claim 1 of the formula, ##STR39##